ISSN 1941-5923

© Am J Case Rep, 2016; 17: 774-781

DOI: 10.12659/AJCR.899754

Received: 2016.05.26
Accepted: 2016.07.11 High-Dose Intravenous Vitamin C Treatment of a
Published: 2016.10.24
Child with Neurofibromatosis Type 1 and Optic
Pathway Glioma: A Case Report
Contribution:
Authors’ ABCDEF 1 Nina Mikirova 1 Department of Research, Riordan Clinic, Wichita, KS, U.S.A.
Study Design  A D 2 Ronald Hunnunghake 2 Department of Clinics, Riordan Clinic, Wichita, KS, U.S.A.
Data Collection  B 3 Department of Laboratory Analysis, Riordan Clinic, Wichita, KS, U.S.A.

Statistical Analysis  C BCDEF 1 Ruth C. Scimeca 4 Department of Research, Inc., Riordan-McKenna Institute, Panama City, Panama
Data Interpretation  D DE 3 Charles Chinshaw
Manuscript
Preparation  E D 3 Faryal Ali
Literature Search  F
Collection  G
Funds B 2 Chris Brannon
DG 4 Neil Riordan

Corresponding Author: Nina Mikirova, e-mail: nmikirova@riordanclinic.org

Conflict of interest: None declared

Patient: Male, 1
Final Diagnosis: Optic glioma
Symptoms: Visual problems
Medication: —
Clinical Procedure: Intravenous vitamin C
Specialty: Oncology

Objective: Unusual clinical course

Background: In neurofibromatosis type 1 (NF1) disease, the loss of the tumor suppressor function of the neurofibromin gene
leads to proliferation of neural tumors. In children, the most frequently identified tumor is the optic pathway
glioma.
Case Report: We describe the case of a 5-year-old child who was diagnosed with NF1 and optic pathway tumor onset at the
age of 14 months. Because of the tumor progression, chemotherapy with carboplatin and vincristine was pre-
scribed at this early age and continued for one year. As the progression of disease continued after chemother-
apy, the child, at the age of 2.8 years, was started on high-dose intravenous vitamin C (IVC) treatment (7–15
grams per week) for 30 months. After 30 months, the results of IVC treatments demonstrated reduction and
stabilization of the tumors in the optic chiasm, hypothalamus, and left optic nerve according to radiographic
imaging. The right-sided optic nerve mass seen before IVC treatment disappeared by the end of the treatment.
Conclusions: This case highlights the positive effects of treating NF1 glioma with IVC. Additional studies are necessary to
evaluate the role of high-dose IVC in glioma treatment.

MeSH Keywords: Ascorbic Acid • Neurofibromatosis 1 • Optic Nerve Glioma

Full-text PDF: http://www.amjcaserep.com/abstract/index/idArt/899754

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Mikirova N. et al.:
High-dose intravenous vitamin C in glioma
© Am J Case Rep, 2016; 17: 774-781
Background
Neurofibromatosis (NF) is an autosomal dominant disorder with
a high mutation rate and a prevalence of around 30/100,000 of
the population [1]. The National Institutes of Health (NIH) di-
vide neurofibromatosis into type 1 (NF1 or von Recklinghausen
syndrome) and type 2 (NF2, acoustic neurofibromatosis, or
central neurofibromatosis). The genetic defect in NF1 is usu-
ally a mutation in the neurofibromin gene on chromosome 17
(17q11.2). The most common features of the disease include
multiple neural tumors (neurofibromas) on the skin or within
the body, and pigmented skin lesions.
Neurofibromin normally functions to down-regulate the p21
Ras oncoprotein. The loss of the tumor suppressor function
of neurofibromin leads to proliferation of neural tumors. NF1
is a common inherited cancer predisposition syndrome, in
which affected individuals are prone to the development of
brain tumors [2].
In children, the most frequently identified brain tumor is the
optic pathway glioma (OPG) [3,4]. Optic nerve gliomas occur in
12% of patients with NF1, with most of these occurring within
the first decade of life and progressing to visual loss or other
neurologic symptoms [5].
OPGs are low-grade glial fibrillary acidic protein immunoreac-
tive tumors that typically affect the prechiasmatic optic nerves
and chiasm [6,7]. Images exposing optic nerve gliomas may
also reveal high signal intensity lesions in the basal ganglia,
thalamus, or cerebellum [8, 9], which was the case discussed
in the present report.
Determining when to treat young children with NF1-associated
OPGs is a challenging clinical problem. As these tumors are
grade 1 pilocytic astrocytomas that do not have malignant po-
tential themselves, it has been argued recently that genotox-
ic chemotherapy and neurotoxic radiotherapy are not indicat-
ed in these cases [10].
In cases of progressive disease, traditional radiotherapy is
contraindicated and is not recommended now, as it leads to
a poorer neuropsychological outcome, secondary tumors, vas-
cular complications, and long-term adverse effects [11,12].
Chemotherapy treatment was introduced in the 1990s to post-
pone or replace irradiation in the management of children with
this type of tumor, and it has become the mainstay treatment for
children with progressive OGPs. There have been a number of
studies that show visual and radiological stabilization in children
with progressing OPG who receive chemotherapy, and a num-
ber of phase I and II trials in the United States are looking for
new treatments for OPG with new chemotherapy drugs [13,14].
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Some studies have shown the efficacy of chemotherapy in in-
ducing tumor response, but administration of chemothera-
py can lead to undesirable side effects [15–18]. The accepted
drugs for NF1 with optic glioma are carboplatin with vincris-
tine. During carboplatin treatment, 30–40% of patients devel-
op hypersensitivity in the form of rash, and the side effects
of vincristine treatment are peripheral (outside the brain and
spinal cord) nerve damage.
In 1976 Linus Pauling proposed the treatment of cancer patients
with intravenous vitamin C (IVC), followed by oral maintenance.
Vitamin C (ascorbic acid, ascorbate), especially at high phar-
macological concentrations, has a long and widely discussed
history in treating cancer [19–25]. According to our studies
and studies by other research groups of high-dose ascorbic
acid and cancer [26], there are several advantages in the treat-
ment of such patients with IVC. The IVC therapy is toxic to tu-
mor cells, but not to normal cells; it can suppress angiogenesis
and inflammation, boost the immune system, cause differen-
tiation of cells, and improve quality of life of cancer patients.
In this report we document a NF1 optic glioma case treated
by IVC after conventional treatment.
Future clinical studies of patients with similar conditions are
warranted to prove the benefits of this type of alternative ther-
apy before or after conventional treatment.
Case Report
A 3-year-old Caucasian male affected by NF1 was brought to
the clinic because of a history of chiasm optic glioma. The di-
agnosis was made at the age of 14 months by magnetic reso-
nance imaging (MRI). At that time, the patient was diagnosed
with optic glioma of the left optic nerve and a small right op-
tic glioma. The patient was previously diagnosed with NF1 at
three months of age. No other pathological findings were doc-
umented at the general physical and neurological examina-
tion. Furthermore, due to his age and poor cooperation, the
visual function was not evaluated.
Because of the clinical and neuro-radiological progression of the
tumor, at the age of 14 months the child started chemothera-
py (carboplatin and vincristine), according to the International
Society of Pediatric Oncology protocol for progressive low-grade
glioma. The treatment consisted of weekly treatment for ten
weeks, and then continued with eight cycles consisting of four
weeks of chemotherapy with 21 days off during 15 months.
Descriptions of the diagnostic imaging reports during chemo-
therapy are presented in Table 1. MRI results demonstrated
the “continued optic pathway with a slight increase in size and
775
 Mikirova N. et al.:
High-dose intravenous vitamin C in glioma
© Am J Case Rep, 2016; 17: 774-781

Table 1. Description of the diagnostic imaging reports during treatments.

No. of IVC
Date Treatment Summary of MRI
treatments
Start of
2/21/2012
chemotherapy
Large left optic nerve glioma, new faint enhancements to the optic nerve,
possible extension of the optic glioma, small right optic glioma with focal
07/05/2012 Chemotherapy
enlargement and enhancement, increased abnormal T2 signal in the right
cerebellum
More prominent contrast enhancement in the left optic nerve in comparison
10/23/2012 Chemotherapy with 07/05/12; optic pathway tumor was decreased in comparison with 4/5/12
and 7/5/12 from 8×8 mm to 6×6 mm
Continued optic pathway tumor with a slight increase in size and degree of
04/02/2013 Chemotherapy enhancement within hypothalamic component; stable appearance of the
optical pathway tumor
End of
04/05/2013
chemotherapy
Stable extent of optic pathway tumor with the increase in size of the enhancing
portion of the tumor centered in the hypothalamic/chiasmatic regions; there
06/25/2013 are enlargement and tortuosity of the left optic nerve and enlargement of the
optic chiasm and hypothalamic region with extension into the bilateral optic
tracts

08/08/2013 Start of IVC

Slight decrease in size of the enhancing hypothalamic and optic pathway

of glioma compared to 09/27/13; improvement in the basal ganglia T2
12/20/2013 7.5 g, 10 g, 15 g 16 signal abnormality from myelin vacuolization; unchanged enlargement and
tortuosity of the left optic nerve; mild enlargement of the right optic nerve was
unchanged
Stable mass centered in hypothalamus and posterior optic chiasm; no new area
2/27/2015 15 g 43 of abnormal enhancement; multiple small scattered T2 signal hyperintensities
including cerebellar signal are all unchanged to slightly improved
The measurements are very similar to the prior with a few of the
measurements slightly smaller on today’s study; no abnormal contrast
8/21/2015 15 g 20
enhancement is visualized within the optical nerve itself; the right nerve is
normal in appearance
Stable tumor involving the hypothalamus, optic chiasm, and left optic nerve;
02/18/16 15 g 27 stable signal changes involving the brain compatible with the patient’s history
of NF1; no right-sided optic nerve mass is seen

degree of enhancement within hypothalamic component and
more prominent contrast enhancement in the left optic nerve.”
Five months after chemotherapy, on 07/05/2012, the diag-
nostic MRI reported that the “largest focus within the interior
right cerebellum measured 8×8 mm in comparison with 5×3
mm on the prior study in April 2012. There was the marked
enlargement of the left optic nerve secondary to the optic gli-
oma, involving the entire length of the optic nerve and ex-
tending posteriorly into the orbital apex. The mild interval in-
creased enlargement of the optic chiasm was observed when
compared with the prior image. The right optic nerve contin-
ued to be mildly enlarged.”
The diagnostic images on 10/23/2012 (8 months after che-
motherapy) again demonstrated optic pathway tumor with
enlargement and tortuosity of the left optic nerve. Abnormal
patchy contrast enhancement was presented within the re-
gion of the hypothalamus, optic chiasm, and bilateral optic
tract. The left optic nerve portion of the optic pathway tumor
was decreased in comparison with the images from the be-
ginning of chemotherapy (6×6 mm; previous measurements
were 8×9 mm).
The increase of the abnormal T2 bright foci within the bilat-
eral cerebellum and decrease of the left optic portion of optic
pathway tumor during chemotherapy are shown in Figure 1.

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Mikirova N. et al.:
High-dose intravenous vitamin C in glioma
© Am J Case Rep, 2016; 17: 774-781

Size of the abnormal bright foci within cerebellum Tretment schedulle of the patient
and left aptic pathway tumor during CT treatment
80 16
Left optic nerve pathway tumor
Abnormal bright foci within cerebellum
70
14
60

50 12
Size of tumor (mm2)

IVC (grams)
40
10
30

20
Start of CT

End of CT
8

10
2012

2013

IVC (grams)
0 6
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 0 500 1000 1500
Months 2/12/12 4/5/13 Days 2/3/16

Figure 1. T
 he changes of the abnormal T2 bright foci within Figure 2. Treatment schedule of the patient.
the bilateral cerebellum and decrease of the left
optic portion of the optic pathway tumor during hand movement, etc.), but the mother decided to find alter-
chemotherapy treatment.
native treatment.

At the end of the chemotherapy on 04/02/13, MRI demon- The patient came to the clinic four months after chemotherapy
strated optic pathway tumor with enlargement and tortuosity on 08-08-2013. Laboratory tests were performed to evaluate
of the left optic nerve, and enlargement of the hypothalamus his levels of vitamin C, vitamin D, inflammation (C-reactive pro-
and optic chiasm. The chiasmatic portion appeared slight- tein), and allergic reaction to food by cytotoxic test. Except for a
ly more prominent, measuring 19×15×17 mm in comparison low level of vitamin D (30 ng/mL, normal range 40–80 ng/mL),
with the previously measured 17×11×12 mm. The portion of all other evaluated parameters were in the normal range. The
tumor involving the hypothalamus demonstrated enlargement. complaints at the first visit were mood swings, poor concen-
There was a more prominent area of enhancement measuring tration, night sweats, muscle weakness, impaired vision, teeth
12×11×9 mm in comparison with the previous size of 4×5×3 grinding, and frequent infections (bronchitis).
mm. During chemotherapy when the patient was 32 months
of age, the MRI showed that the size of the tumor centered The patient received IVC injections once per week (7 g at the
within the hypothalamic and chiasmatic regions was stable, first visit, 10 g the next 4 weeks, and after that 15 g per week,
but the enhancing component of this tumor was increased in for a total of 100 treatments). All periods of IVC treatment and
size, measuring 2.1×1.9×1.6 cm in comparison with prior mea- chemotherapy are shown in Figure 2. The bar shows the dura-
surements of 1.4×1.7×.4 cm. tion of the initial chemotherapy, and each square represents
the high-dose IVC injection. The values on the X-axis corre-
The examination by the ophthalmologist showed that child did spond to the amount of injected vitamin C in grams.
not have any peripheral vision in his left eye. It wasn’t known
whether or not he could see with his left eye because he was Table 1 shows a summary of the MRI reports, the number
unable to localize it. of IVC treatments between MRIs, and the dosages of inject-
ed vitamin C.
The oncology doctor who had seen the patient was very con-
cerned about the optic pathways, which were torturous on his The level of ascorbic acid in blood was measured 3 times (af-
left eye, extension of the tumor into the chiasm and into the ter 7 g, 10 g, and 15 g of vitamin C) and reached 190 mg/dL-
right optic nerve, and the progression of tumor growth. The 210 mg/dL, which was 100 times higher than the pre-treat-
doctor discussed with the parents additional treatments such ment level.
as radiation or a different type of chemotherapy that could
cause different side effects (nerve problems, ability to walk,

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 Mikirova N. et al.:
High-dose intravenous vitamin C in glioma
© Am J Case Rep, 2016; 17: 774-781

previous measurements of 2×1.6×2 cm at the beginning of

Size of hypothalamic/optic chiasm tumor during treatment the IVC treatment.
7000

Changes in the hypothalamic component before and during

6000 IVC treatment are shown in Figure 3 and demonstrate the re-
duction in the size of tumor during IVC treatments. According
5000 to the data in Figure 3, the size of hypothalamic/optic chiasm
tumor had increased about two times at the end of chemo-
4000 therapy, remained the same size at the beginning of the IVC
Size (mm3)

treatment, and decreased about five times during two years

3000 of IVC treatment.

2000 After 2.5 years of the treatment by IVC at the clinic, the pa-
Start of IVC

tient had an MRI in August 2015 and in February 2016. The re-
End of CT

sults are presented in Table 1 and are shown before and after
1000
treatment in Figure 4A and 4B. The MRIs (sagittal view) dem-
2013

2014

2015

onstrate a hyperintense mass (hypothalamic/optic chiasm tu-

0 1 2 3 4 5 6 7 8 9 101112 1314 1516 1718192021 22232425 2627282930 3132333435 36 mor and optic pathway tumor) before IVC treatment (Figure
Months 4A) and reduced intensity after treatment (Figure 4B). Circled
areas in figures indicate the chiasmatic/hypothalamic path-
Figure 3. C
 hanges of the hypothalamic/optic chiasm tumor ways before and after treatment. The left optic nerve shows
during chemotherapy and IVC treatments. hyperintensity on both images with decreased and stable ap-
pearance after treatment.
After 4 months with a total of 16 IVC treatments, MRI dem-
onstrated that the post-chiasmatic T2 hyperintensity involv- In August 2015 the patient’s oncology doctor stated that the
ing the hypothalamus had visually improved with less exten- tumor was stable, with shrinkage in the chiasm/hypothala-
sion into the bilateral optic pathways. The enhancing portion mus area (1.1×1.1×1.0 cm vs. 1.1×1.2×1.3 cm). The tumor on
of this tumor measured 1.8×1.3×1.6 cm in comparison with the left optic nerve was still considered enlarged and tortuous.

A B

Figure 4. M
 agnetic resonance images before (A) and after (B) IVC treatment. Circled areas show the optic chiasm and hypothalamic
region.

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High-dose intravenous vitamin C in glioma
© Am J Case Rep, 2016; 17: 774-781
Half a year later in February 2016 the oncology doctor recom-
mended, based on the results of shrinkage and stability of the
tumor over the past two and a half years of IVC treatment,
continuation of the treatment and reevaluation in one year.
The patient still comes to the clinic weekly and continues high-
dose IVC treatment. The patient is monitored by our doctors,
and there have been no complications caused by the treatment.
Discussion
We present a case report of a patient with NF1 and optical gli-
oma who had high-dose IVC treatment about three years after
one year of conventional treatment (carboplatin and vincris-
tine). To our knowledge it is the first case report of a NF1 pa-
tient with OPG treated intravenously by high-dose vitamin C,
as an extensive literature review did not reveal cases of chil-
dren with NF1 and OPG treated by IVC.
The results of the MRI analysis during and at the end of che-
motherapy showed the continued optic pathway tumor with
a slight increase in size and degree of enhancement within
the tumor centered in the hypothalamic/chiasmatic regions.
Approximately 4 months after completion of chemotherapy,
the patient started treatment at the Riordan Clinic with high-
dose IVC (7.5–15 g) one time per week.
As nutritional evaluation of vitamin levels demonstrated low
vitamin D, a dose of vitamins D3/K2 5000 IU/50 µg per day
was prescribed. At the end of the treatment, the patient’s level
of vitamin D increased from 30 ng/mL to 120 ng/mL. Diet im-
provements were recommended with addition of fruits, veg-
etables, and a shake supplement with proteins, vitamins, and
essential minerals.
The improvement of the patient’s condition after 2.8 years
of treatment at the clinic was described based on diagnostic
MRI reports in Table 1 and Figures 3 and 4. There was shrink-
age/stabilization of the tumors in the hypothalamus, optic chi-
asm, and left optic nerve according to radiographic imaging.
The right optic nerve that showed initial enlargement demon-
strated normal appearance according to the last two MRI re-
ports made during IVC treatments.
The patient was treated according to the Riordan Protocol,
which involves the slow infusion of high-dose IVC [26]. This
protocol is used by many integrative and orthomolecular prac-
titioners for treating a variety of conditions, such as combat-
ing infections, treating chronic diseases, and in cancer care.
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Our clinic has treated thousands of cancer patients for more
than forty years using this protocol. The rationales for using in-
travenous ascorbate infusions to treat cancer, based on our stud-
ies and experience, are summarized in reference 26. According
to the studies, ascorbic acid is a key water-soluble antioxidant
that, when administered in doses well above its recommended
dietary allowance, may have preventative and therapeutic val-
ue against a number of pathologies. Ascorbic acid is essential
for the formation of collagenase, a basic substance of connec-
tive tissue, which may be related to corneal wound healing and
prevention of cerebral tissue degeneration [27,28].
In one study, the anti-proliferative and apoptotic effects of
ascorbic acid on T98G glioma cells through modulation of
IGF-IR expression and consequent facilitation of programmed
cell death were reported [29]. A previous study showed up-
regulation of proteolipid protein (PLP) and myelin-associat-
ed glycoprotein (MAG) genes in ascorbic acid–treated rat gli-
oma C6 cells [30].
Our studies have demonstrated that IVC treatment of cancer
patients has an anti-inflammatory effect and anti-angiogen-
ic effects [31–33].
It is now shown that ascorbic acid has much a broader impact
on the critical stages of tumor cell proliferation and differenti-
ation by shifting their epigenome and transcriptome. For ex-
ample, nuclear factor erythroid 2-related factor 2 (Nrf2) is an
essential component of cellular defense against a variety of
endogenous and exogenous stresses. A marked increase in
research over the past few decades focusing on Nrf2 and its
role in regulating glioblastoma has revealed the potential val-
ue of Nrf2 in the treatment of glioblastoma and that ascorbic
acid affects the regulation of this factor [34].
Ascorbate plays an important role in regulation of hypoxia-in-
ducible factor 1 (HIF-1a), the dramatic overexpression of which
has been observed in common cancers, cancer cell lines, and
metastases [35]. Ascorbate has been shown to assist prolyl
and lysyl hydroxylases in the hydroxylation of HIF-1a, a tran-
scription factor responsible for the cellular response to low ox-
ygen conditions through activation of genes controlling sev-
eral cellular transduction pathways, by regulating growth and
apoptosis, cell migration, energy metabolism, angiogenesis,
and transport of metal ions and glucose [36]. Because HIF-1a
prolyl hydroxylase is stimulated by ascorbic acid, low vitamin
C levels would reduce HIF-1a hydroxylation and thereby pro-
mote HIF-dependent gene transcription and tumor growth [37].
Given the fact that IVC boosts immunity and collagen formation,
inhibits hyaluronidase involved in metastasis, induces apopto-
sis to help program death of cancer cells without harm to nor-
mal cells, has anti-inflammatory and anti-angiogenic effects,
779

and improves quality of life of cancer patients, this treatment
can be considered as therapy in optic glioma.
In addition to the IVC treatment, supplementation with vita-
min D may have a positive effect on the patient’s condition.
Vitamin D receptors have important effects not only on phys-
iological processes related to calcium metabolism, but also on
cell growth and differentiation. There is in vitro evidence that
vitamin D metabolites might be useful agents in the differen-
tiation therapy of human malignant gliomas [38,39]. The ma-
jor biologically active metabolite of vitamin D has shown a cy-
totoxic effect on rat and human glioma cells [40].
As scientific evidence suggests that the glioma’s degree of ag-
gressiveness can be modulated by dietary interventions and
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© Am J Case Rep, 2016; 17: 774-781
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In conclusion, in this report we document an optic glioma case
associated with NF1 treated by IVC after conventional treat-
ment. This treatment may be recommended for young patients
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